Abstract There is a growing consensus that protection against HIV infection will require BOTH antiviral antibody responses as well as polyfunctional CD4+ and CD8+ T cells with potent lytic activity. To stimulate the breadth, potency, and rate of response required, Profectus Biosciences intends to utilize its platform technologies based on DNA vaccines combined with genetic adjuvants. As a step in that direction, a phase 1 clinical trial, HVTN- 080, showed that electroporation in combination with our IL-12 adjuvant can double the CD4+ and CD8+ T cell response rate in vaccinees over electroporation alone1. Even with this success, we recognize that a truly effective HIV vaccine will require a regimen that can consistently provide high magnitude, long-lived responses at rates >95% with as few booster immunizations as possible. We believe that adjuvants are a key to developing such a vaccine. Under our phase I SBIRs, we identified a new class of genetic adjuvants that exploit the RIG-I signaling cascades and trigger potent anti-viral innate immune responses. These innate responses integrate with TLR evoked innate responses and DAMPs/alarmins to evoke potent anti-viral adaptive immune responses. Also under phase I, we found that the adjuvants attenuated vaccine antigen expression by negatively impacting the promoter. We have now developed an improved promoter to drive our vaccine antigen and adjuvant expression that is not attenuated by these adjuvants. Under this phase II SBIR, we intend to identify an optimal combination of DNA adjuvants using a macaque model. Upon completion of phase II, we expect to have identified a lead adjuvant combination worthy of testing with our HIV vaccine in phase I human trials. 2